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Review
. 2019 Apr 20;46(4):187-199.
doi: 10.1016/j.jgg.2019.03.010. Epub 2019 Apr 23.

Die in pieces: How Drosophila sheds light on neurite degeneration and clearance

Maria L Sapar  1 , Chun Han  2
Affiliations
Review

Die in pieces: How Drosophila sheds light on neurite degeneration and clearance

Maria L Sapar et al. J Genet Genomics. .

Abstract

Dendrites and axons are delicate neuronal membrane extensions that undergo degeneration after physical injuries. In neurodegenerative diseases, they often degenerate prior to neuronal death. Understanding the mechanisms of neurite degeneration has been an intense focus of neurobiology research in the last two decades. As a result, many discoveries have been made in the molecular pathways that lead to neurite degeneration and the cell-cell interactions responsible for the subsequent clearance of neuronal debris. Drosophila melanogaster has served as a prime in vivo model system for identifying and characterizing the key molecular players in neurite degeneration, thanks to its genetic tractability and easy access to its nervous system. The knowledge learned in the fly provided targets and fuel for studies in other model systems that have further enhanced our understanding of neurodegeneration. In this review, we will introduce the experimental systems developed in Drosophila to investigate injury-induced neurite degeneration, and then discuss the biological pathways that drive degeneration. We will also cover what is known about the mechanisms of how phagocytes recognize and clear degenerating neurites, and how recent findings in this area enhance our understanding of neurodegenerative disease pathology.

Keywords: Axon; Dendrite; Drosophila; Injury assay; Neurite degeneration; PS exposure; Phagocyte; Phagocytosis; Wallerian degeneration.

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Figures

Fig. 1:
Fig. 1:. Neurite injury assays in Drosophila Melanogaster.
A: The olfactory receptor neurons (ORN) injury assay showing a sagittal view of the fly olfactory system. ORNs are damaged by removal of peripheral organs, antenna and maxillary palps, where neuron cell bodies are located. Maxillary palp ORNs (magenta) project fewer axons into the antennal lobe than antennal ORNs (green). Injured axons begin to show signs of degeneration by day 1 post axotomy and are mostly cleared away by day 3. Glial membrane infiltration can be detected by day 1 post axotomy. B: The larval axon injury assay. Motor neurons are damaged by pinching the larva with forceps. The axons distal to the injury site degenerate. C: The wing clipping assay. Glutamatergic sensory neuron cell bodies are located along the anterior margin of the wing and their axons run in parallel in a bundle called L1 vein towards the fly body. Clipping the wing results in axon degeneration distal from the cut site. Axons can be imaged where L1 vein ends in the proximal part of the wing. D: The larval dendrite injury assay. Sensory da neuron dendrites innervate the basal side of the larval epidermis. Using a high energy laser, injury can be induced on a single dendrite branch. Injured dendrites degenerate distal to the cut site and their debris is engulfed by epidermal cells.
Fig. 2:
Fig. 2:. Injury-induced neurodegeneration pathway.
In the core pathway, injury induces accumulation of Hiw/Phr1, which in turn destabilizes Nmnat. The loss of Nmnat results in accumulation of NMN and reduction of NAD+. High levels of NMN and low levels of NAD+ likely contribute to the activation of dSarm/SARM1, which further depletes NAD+ and commits the axon to degeneration possibly by activating Axed. Wnd/DLK and the JNK pathway promote axon death downstream of dSarm/SARM1, likely also downstream of Axed. Peb promotes degeneration but its position in the pathway is unclear. The green arrows represent activation; magenta lines represent blocking. Gray arrows represent uncertain activation.
Fig. 3:
Fig. 3:. The association of PS exposure and neurite degeneration.
A: Phosphatidylserine (PS) exposure resulting from neurite degeneration. In the PNS, injured dendrites (magenta) expose high levels of PS (green) which is recognized via engulfment receptor (blue) on phagocytic epidermal cells. Epidermal cells clear away the injured dendrites but spare the rest of the dendritic arbor. In the CNS, glia engulf degenerating axons by recognizing exposed PS. B: Ectopic PS exposure as a cause of neurite degeneration. When PS asymmetry is perturbed, such as by the loss of PS flippase function or by scramblase activation, neurons expose low levels of PS at the distal dendritic arbor. This is sufficient to drive epidermal cells to attack and engulf the PS exposing dendrites. In the CNS, ectopic PS exposure also results in loss of axon membranes. PNS, peripheral nervous system; CNS, central nervous system.
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